CN116332777A - Diaryl benzyl methylamine compound, preparation and application as carrier in synthesizing polypeptide - Google Patents

Diaryl benzyl methylamine compound, preparation and application as carrier in synthesizing polypeptide Download PDF

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CN116332777A
CN116332777A CN202310138155.0A CN202310138155A CN116332777A CN 116332777 A CN116332777 A CN 116332777A CN 202310138155 A CN202310138155 A CN 202310138155A CN 116332777 A CN116332777 A CN 116332777A
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amino acid
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朱锦涛
杜钶涵
蒋皓
杨卓燃
周增太
夏建新
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Xiangyang Weien Biotechnology Co ltd
Huazhong University of Science and Technology
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Huazhong University of Science and Technology
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Abstract

The invention relates to a diaryl benzyl amine compound, preparation and application of the diaryl benzyl amine compound as a carrier for synthesizing polypeptide, and relates to the field of polypeptide synthesis and the field of antibiosis. The invention provides the application of diaryl benzyl amine compound as soluble carrier in liquid phase synthesis of polypeptide chain, which is used as initial template reagent to couple amino acid in sequence to construct polypeptide chain and finally remove the template under mild condition. The provided amphiphilic antibacterial peptide has short sequence length, simple composition, high-efficiency broad-spectrum antibacterial activity and good prospect and application value in the fields of polypeptide chemistry and antibacterial.

Description

Diaryl benzyl methylamine compound, preparation and application as carrier in synthesizing polypeptide
Technical Field
The invention relates to the field of polypeptide synthesis and the field of antibiosis, in particular to a diaryl benzyl amine compound, preparation and application of the diaryl benzyl amine compound as a carrier for synthesizing polypeptide, and relates to an amphiphilic antimicrobial peptide, and sequence design and preparation thereof.
Background
In recent years, due to single and long-term wide use of traditional antibiotic targets, the evolution speed of multi-drug resistant bacteria is accelerated, so that a plurality of bacteria generate drug resistance. In addition, the cost of current antibiotics is increasing, and the development speed of new antibiotics is far behind the emergence speed of new resistant bacteria. Therefore, there is an urgent need to develop antibacterial drugs that are highly effective, low-toxic, and do not induce bacterial resistance.
Among them, antibacterial peptides have attracted attention from many researchers over the last two decades as an important component of the natural immune system. The main bactericidal mechanism of the antibacterial peptide is as follows: by electrostatic action approaching the cell membrane, destroying its integrity and creating a perforation phenomenon, causing the cell contents to overflow and die. The rapid membrane dissolution mechanism enables the antibacterial peptide to act on a plurality of targets, has broad-spectrum antibacterial activity, reduces the possibility of producing drug-resistant strains, and is expected to become a new generation of efficient antibacterial drugs. However, the natural antibacterial peptide has long sequence and high synthesis cost; the antibacterial activity is relatively low; is easy to be degraded by protease, etc. In order to make up for the defects of the natural antibacterial peptide, the beneficial characteristics of the antibacterial peptide are reserved and optimized, and the design of the amphiphilic antibacterial peptide with simple sequence, which can be artificially and chemically synthesized, provides great help for the research and development and application of the novel antibacterial peptide.
The chemical synthesis of polypeptides is largely divided into two pathways: solid phase synthesis and liquid phase synthesis. In the early development stage of polypeptide chemistry, the polypeptide synthesis reaction is generally carried out in a liquid phase, but the traditional liquid phase synthesis method is difficult to separate and purify and complicated in post-treatment. Thus, in 1963, the American well-known biochemist Robert Bruce Merrifield proposed polypeptide synthesis on solid phase resins. The solid-phase polypeptide synthesis method effectively avoids complex separation and purification steps of liquid-phase polypeptide synthesis, and has obvious superiority: (1) In the polypeptide synthesis process, a polypeptide chain is connected to polymer resin, and the obtained product polypeptide is insoluble and is easy to wash and filter; (2) Excess reagents and byproducts of the reaction process can be removed by washing and filtration; (3) The whole reaction is carried out in the same container, so that the loss caused by multiple precipitation, washing and separation is avoided, and the operation is simple and convenient; the operation (4) has strong repeatability.
However, solid phase synthesis also has some problems: (1) The sequence of the synthesized polypeptide is short, and when the number of peptide chain residues exceeds 50, the synthesis of the peptide chain is limited to a certain extent; (2) long synthesis time; and (3) the synthesis efficiency and purity are low, and the cost is high. With increasing amino acid number, synthesis efficiency gradually decreases, non-target polypeptide content gradually increases, target polypeptide purity gradually decreases, and subsequent purification and repeatability are increasingly difficult. The raw materials such as resin and protective amino acid for synthesizing the polypeptide are expensive, the synthetic cost of the polypeptide is high, and the requirement of commercial production cannot be completely met.
In recent years, scientists have devised a class of polypeptide synthesis using a combination of solid phase and liquid phase synthesis in order to improve the shortcomings of conventional solid phase synthesis methods. By designing a soluble carrier with a specific structure, amino acid coupling is performed in a liquid phase, and polypeptide synthesis is performed by combining solid phase and liquid phase synthesis intermediate purification and post-treatment methods, so that the production scale and purity of the polypeptide are greatly improved, and large-scale production is realized.
In view of the problems, the invention provides a liquid-phase polypeptide synthesis method with simple operation and high yield, and an amphiphilic antibacterial peptide with short sequence and simple composition. Mainly solves the problems of more steps, long time consumption and high production cost of the prior polypeptide synthesis and provides a means for solving the drug resistance of bacteria. Has important functions in polypeptide synthesis and bacterial infectious diseases treatment.
Disclosure of Invention
The invention provides the diaryl benzyl amine compound and the preparation method thereof, which have the advantages of simple and easily obtained raw materials, low cost, mild and simple preparation steps. The carrier is used as the initial end of the polypeptide chain, so that the coupling of difficult amino acid can be realized, and the advantages of simple purification, low cost and high yield exist, and finally the polypeptide chain with amidated C end is obtained. Solves the technical problems of more steps, long time consumption and high production cost in the polypeptide synthesis in the prior art.
According to a first aspect of the present invention, there is provided a diarylbenzeneamine compound having the structural formula shown in formula i:
Figure BDA0004086693520000031
wherein R is an alkyl chain of C12-C22.
According to another aspect of the present invention, there is provided a method for preparing the diarylbenzenemethanamine compound, wherein the reaction formula is as follows:
Figure BDA0004086693520000032
wherein R is a C12-C22 alkyl chain, and X is halogen;
the preparation method comprises the following steps:
a. dissolving a substance shown in a formula 1, and adding a substitution reaction reagent RX and an acid binding agent to perform substitution reaction to generate a compound 2;
b. adding the compound 2, a reducing agent and a cosolvent into a solvent, and carrying out a reduction reaction to generate a compound 3;
c. dissolving the compound 3, adding a substitution reaction reagent of carbamic acid ethyl ester and a catalyst, and carrying out substitution reaction to generate a compound 4;
d. dissolving the compound 4, adding alkali liquor and cosolvent, and carrying out hydrolysis reaction to obtain the compound shown in the formula I.
Preferably, in the step a, the acid binding agent is one or a mixture of more than two of anhydrous potassium carbonate, anhydrous sodium carbonate, pyridine, diisopropylethylamine and triethylamine; the solvent is one or more than two of DMF, DMAc, DMSO, THF, NMP and toluene; the ratio of the amounts of compound 1, substitution reagent RX and acid-binding agent substance was 1.0: (4.0 to 4.5): (6.0-8.0), the substitution reaction temperature is 70-100 ℃, and the substitution reaction time is 16-20 hours.
Preferably, in the step b, the reducing agent is sodium borohydride, lithium aluminum hydride or borane, and the solvent is one or a mixture of more of THF, toluene and xylene; the amount of the substances of the compound 2 and the reducing agent is 1.0: (4.5-5.0), the temperature of the reduction reaction is 60-80 ℃, and the reduction reaction time is 4-6 hours;
preferably, in the step c, the catalyst is methane sulfonic acid, and the solvent is a mixture of one or more of THF, toluene and xylene; the ratio of the amounts of compound 3, substitution reagent urethane and catalyst material was 1.0: (2.0-2.5): (0.2-0.5), the substitution reaction temperature is 100-120 ℃, and the substitution reaction time is 3-6 hours.
Preferably, in the step d, the alkali liquor is sodium hydroxide, the solvent is a mixture of one or more of THF, toluene and xylene, the cosolvent is methanol or ethanol, and the ratio of the amount of the compound 4 to the amount of the substances of the hydrolysis reaction reagent is 1.0: (7.0-7.5), the hydrolysis reaction temperature is 100-120 ℃, and the hydrolysis reaction time is 16-20 hours.
According to another aspect of the invention, there is provided the use of said diarylbenzenemethanamine-based compounds as soluble carriers in the liquid phase synthesis of polypeptide chains.
Preferably, the application is specifically: the method comprises the steps of taking a compound shown in a formula I as a soluble carrier, activating a carboxyl component by an activating agent, condensing the carboxyl component with amino acid through a condensing agent under an alkaline condition to remove an amino protecting group, continuously coupling the next amino acid until the synthesis of polypeptide is completed, and finally cracking the carrier to obtain a polypeptide chain which does not contain an initial terminal carrier and is amidated at the N terminal.
According to another aspect of the present invention, there is provided an amphiphilic antimicrobial peptide having the amino acid sequence (AB) n Wherein n is an integer of 3 to 6, A is a cationic hydrophilic amino acid, and B is a hydrophobic amino acid;
preferably, the polypeptide chain is an amphiphilic antimicrobial peptide sequence (AB) n Wherein n is an integer of 3 to 6, A is a cationic hydrophilic amino acid, and B is a hydrophobic amino acid;
preferably, the cationic hydrophilic amino acid is lysine, arginine or histidine; the hydrophobic amino acid is leucine, isoleucine, phenylalanine, alanine, valine or tryptophan.
According to another aspect of the invention, there is provided the use of the amphiphilic antimicrobial peptide in the preparation of an antimicrobial drug;
preferably, the bacteria that the medicament can kill are enterococcus faecalis, staphylococcus aureus, methicillin-resistant staphylococcus aureus, salmonella or escherichia coli; the fungus which can be killed by the medicine is candida albicans.
In general, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) The diaryl benzyl amine compound provided by the invention has the advantages of simple and easily available raw materials and low cost. It is used as a soluble carrier to synthesize polypeptide in liquid phase synthesis, which is used as an initial template agent to sequentially couple amino acids to construct polypeptide chains and finally remove the template under mild conditions. Compared with the traditional solid phase synthesis method for synthesizing the polypeptide, the method has the following advantages: (1) all reactions in the synthesis method are carried out in the solution, so that the method is a homogeneous reaction, saves reaction raw materials, has high reaction speed, is easy to detect the reaction endpoint by TLC technology, and reduces cost and saves time; (2) after the reaction of each step is finished, the excessive reactant can be washed away by adding a poor solvent, and meanwhile, the product is separated out, the purification method is simple and convenient, and the advantages of a solid-phase and liquid-phase synthesis route are combined.
(2) The amphiphilic antibacterial peptide provided by the invention has a short sequence and simple composition, and comprises hydrophilic cationic amino acid and hydrophobic amino acid. The synthetic cost is low, the high-efficiency broad-spectrum antibacterial activity is achieved, and the application prospect in the field of bacterial infection treatment is good. Thus solving the problems of complex sequence, high synthesis cost, poor antibacterial activity and the like of the traditional antibacterial peptide.
Drawings
FIG. 1 shows the synthetic route of the compounds of formula I of the present invention.
FIG. 2 is a synthetic route for synthesizing polypeptide chains of the present invention.
FIG. 3 is a graph showing minimum bactericidal concentration of antimicrobial peptides according to some embodiments of the invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The structure of the diarylbenzenemethanamine compound serving as the liquid-phase polypeptide synthesis carrier is shown as a formula I:
Figure BDA0004086693520000061
wherein R is selected from C12-C22 fatty chains.
In some embodiments of the invention, the compound has the structure shown in formula II:
Figure BDA0004086693520000062
the carrier formula II is shown as the formula C 61 H 109 NO 4 Molecular weight 920.55, designated BDPMA.
The invention provides a preparation method of a liquid-phase polypeptide synthesis carrier, which takes a compound shown in a formula 1 as a raw material, and the carrier is prepared through steps of substitution reaction, reduction reaction, substitution reaction, hydrolysis reaction and the like.
Figure BDA0004086693520000071
Compounds of formula 1, formula C 13 H 10 O 5 Molecular weight 246.22.
The synthetic route of the compound shown in the formula I is shown in figure 1.
The method comprises the following steps:
a) Adding a compound shown in a formula 1, 1-bromododecane and anhydrous potassium carbonate into a solvent DMF, and performing substitution reaction to generate a compound 2, namely a compound shown in a formula 2; wherein the reaction temperature is 80-90 ℃;
the post-treatment process of the step (a) comprises the following steps: slowly adding aqueous hydrochloric acid solution and water to precipitate the compound shown in the formula 2, washing with water and methanol, filtering, and drying.
b) Dissolving a compound shown in a formula 2 in solvents THF and toluene, adding sodium borohydride a small amount of times, and performing reduction reaction to generate a compound 3, namely a compound shown in the formula 3; wherein the reaction temperature is 60-70 ℃;
the post-treatment process of the step (b) comprises the following steps: slowly adding hydrochloric acid aqueous solution into the compound shown in the formula 3 obtained by the reaction, quenching, desolventizing, adding hydrochloric acid aqueous solution and water to regulate pH value for precipitation, and finally washing with water and methanol, filtering and drying to obtain the compound.
c) Dissolving a compound shown in a formula 3, carbamic acid ethyl ester and methylsulfonic acid in toluene as a solvent, and carrying out substitution reaction to generate a compound 4, namely a compound shown in a formula 4; wherein the reaction temperature is 110-120 ℃;
the post-treatment process of the step (c) comprises the following steps: slowly adding anhydrous sodium carbonate into the compound shown in the formula 4 obtained by the reaction to remove the catalyst, desolventizing, adding methanol, washing, filtering and drying to obtain the compound.
d) Dissolving a compound shown in a formula 4 and NaOH in toluene and a small amount of ethanol, and performing hydrolysis reaction to generate a compound III, namely a compound shown in the formula III; wherein the reaction temperature is 100-110 ℃;
the post-treatment process of the step (d) comprises the following steps: extracting the compound shown in the formula III obtained by the reaction with a mixed solution of water, normal hexane and ethyl acetate, washing with water, filtering with water and methanol, and drying.
As a preferred scheme of the invention, in the step a), the acid-binding agent comprises one or a mixture of more than two of anhydrous potassium carbonate, anhydrous sodium carbonate, pyridine, diisopropylethylamine and triethylamine; the substitution reaction reagent a comprises one or a mixture of more than two halogenated alkanes RX, R is a C12-C22 fatty chain, and X is halogen; the solvent is one or more than two of DMF, DMAc, DMSO, THF, NMP and toluene;
in the step a), the mol ratio of the substance shown in the formula 1, the substitution reaction reagent and the acid binding agent is 1.0:4.0-4.5:6.0-8.0, the substitution reaction temperature is 70-100 ℃, and the substitution reaction time is 16-20 hours.
In a preferred embodiment of the present invention, in the step b), the reducing agent includes sodium borohydride, lithium aluminum hydride, and borane; the solvent comprises one or more of THF, toluene and xylene; the mol ratio of the compound shown in the formula 2 to the reducing agent is 1.0:4.5-5.0, the temperature of the reduction reaction is 60-80 ℃, and the reduction reaction time is 4-6 hours.
In a preferred embodiment of the present invention, in step c), the substitution reagent is ethyl aminocaproate, and the catalyst is methanesulfonic acid; the solvent comprises one or more of THF, toluene and xylene; the molar ratio of the compound shown in the formula 3, the substitution reaction reagent b and the catalyst is 1.0:2.0-2.5:0.2-0.5, the substitution reaction temperature is 100-120 ℃, and the substitution reaction time is 3-6 hours.
In a preferred embodiment of the present invention, in the step d), the hydrolysis reagent is sodium hydroxide; the solvent comprises one or more of THF, toluene and xylene; the cosolvent comprises one or a mixture of two of methanol and ethanol; the mol ratio of the compound shown in the formula 4 to the hydrolysis reaction reagent is 1.0:7.0-7.5, the hydrolysis reaction temperature is 100-120 ℃, and the hydrolysis reaction time is 16-20 hours.
The synthetic route of the compound II is as follows:
Figure BDA0004086693520000091
2.0g (8.1 mmol) of the compound of formula 1 and 9.2g (36.6 mmol) of 1-bromododecane were taken, and added to a 500mL three-necked flask, and 100mL DMF was added to the flask, and the mixture was stirred and dissolved, and 8.0g (56.9 mmol) of anhydrous potassium carbonate was further added thereto, and the mixture was heated to 80℃and reacted under reflux for 16 hours. TLC monitored the end of the reaction, and after the end of the run-up reaction, the reaction solution was cooled in an ice-water bath. Under the condition of full stirring, 100mL of 1mol/L hydrochloric acid and 50mL of water are slowly added into the reaction liquid, the stirring is continued for 15min, solid precipitation is performed, then the filtration is performed, and filter cakes are sequentially washed with water and methanol. Vacuum drying at 40℃for 6 hours gave 7.1g of the compound as a white solid in 95.4% yield.
7.1g (7.7 mmol) of the compound of formula 2 was taken, and a 200mL three-necked flask was charged with 100mL THF and 5mL methanol, and the mixture was heated to 60℃and dissolved with stirring, and 1.4g (36.4 mmol) of sodium borohydride was added to the flask a small number of times and reacted under reflux at 60℃for 6 hours. TLC monitored the end of the reaction, and after the end of the run-up reaction, the reaction solution was cooled in an ice-water bath. Under the condition of fully stirring, 20mL of 1mol/L hydrochloric acid is added dropwise to the reaction solution, after the dropwise addition is finished, THF is removed by decompression concentration, 80mL of water is added to the rest reaction solution, and the pH is adjusted to 5-7 by 1mol/L hydrochloric acid. The suspension is fully stirred for 15min, filtered, and the filter cake is washed by water and methanol in turn. Vacuum drying at 40℃for 6 hours gave 6.9g of the compound as a white solid in 97.5% yield.
6.9g (7.5 mmol) of the compound of formula 3, 1.4g (15.1 mmol) of urethane and 0.4g (3.8 mmol) of methanesulfonic acid were taken into a 200mL three-necked flask, 100mL of toluene was added to the flask, and the temperature was raised to 110℃for reflux reaction for 5 hours. TLC monitored the end of the reaction, after the end of the run, the reaction mixture was cooled to room temperature, 0.5g (5.0 mmol) of anhydrous sodium carbonate was added, and toluene was removed by concentration under reduced pressure. To the residue, 100mL of methanol and 25mL of toluene were added, the temperature was raised to 90℃and the mixture was stirred to dissolve well. Naturally cooling the reaction solution to room temperature to precipitate crystals. Filtering, and flushing the filter cake with methanol. Vacuum drying at 40℃for 6 hours gave 7.0g of the compound as a yellow solid in 94.2% yield.
7.0g (7.1 mmol) of the compound of formula 4 and 2.0g (51.1 mmol) of sodium hydroxide were charged into a 200mL three-necked flask, 90mL toluene and 60mL ethanol were added to the flask, and the mixture was dissolved by stirring, and the temperature was raised to 100℃for reflux reaction for 16 hours. TLC monitored the end of the reaction, and after the end of the run-up, the reaction was cooled to room temperature. After cooling, 90mL of water, 60mL of n-hexane and 60mL of ethyl acetate were added, the extraction was allowed to stand for delamination, the aqueous layer was discarded, the organic layer was washed 2 times with 90mL of water, and then the solvent was removed by concentration under reduced pressure. To the residue was added 50mL of water and 50mL of acetonitrile, and the mixture was stirred well for 15min to form a suspension. The mixture was filtered and the filter cake was rinsed with water and acetonitrile. Vacuum drying at 40℃for 6 hours gave 6.0g of the compound as a yellow solid in 91.1% yield. The white solid is a compound II which is an amino resin type soluble hydrophobic liquid phase carrier.
According to a second object of the present invention, there is provided a method for liquid phase polypeptide synthesis, wherein amino acids are coupled in sequence using formula I as a raw material, deprotected to prepare a C-terminal amidated polypeptide chain, and cleaved.
The synthetic route is shown in figure 2.
The polypeptide chain liquid phase synthesis comprises the following steps:
1) Coupling amino acids:
in the technical scheme of the invention, the molar ratio of the compound shown in the formula I to the amino acid is 1:1.1-1.5, and the condensing agent comprises one or more than two of EDC, DCC, DIC, HATU, HBTU, HOAt, HOBt, pyAOP, pyBOP, wherein the preferable one is HOBt/HBTU (1.5-2.0 equiv);
in the technical scheme of the invention, the alkaline condition is provided by one or a mixture of more than two of DIPEA, TEA, DBU, pyridine, lutidine and collidine, wherein DIPEA (3.0-4.0 equiv) is preferable;
the solvent comprises DCM and CHCl 3 THF, of which DCM is preferred.
2) Removing Fmoc:
in the technical scheme of the invention, the deprotection reagent comprises piperidine, 4-methylpiperidine, DBU and diethylamine, wherein the preferred deprotection reagent is 4-methylpiperidine; the solvent comprises DCM and CHCl 3 THF, of which DCM is preferred; the volume ratio of 4-methylpiperidine to DCM was 1:9.
3) Cracking:
in the technical scheme of the invention, the carrier conditions for polypeptide cleavage and liquid phase synthesis are TFA, TIS, H 2 O, preferably TFA, TIS, H 2 O=95:2.5:2.5 (volume ratio).
According to a third object of the present invention, there is provided an amphiphilic antimicrobial peptide comprising from N-terminus to C-terminusThe amino acid sequence of (A) is (AB) n Wherein n is an integer of 3 to 6, A is a hydrophilic cationic amino acid, and B is a hydrophobic amino acid.
As a preferred embodiment of the present invention, the cationic amino acid is lysine, arginine or histidine; the hydrophobic amino acid is leucine, isoleucine, phenylalanine, alanine, valine or tryptophan.
In the technical scheme of the invention, the synthesis method of the amphiphilic antimicrobial peptide is completed by adopting a soluble diaryl benzyl amine compound as a carrier through the liquid phase synthesis route.
The following table shows the reagents used in the present invention:
Figure BDA0004086693520000111
Figure BDA0004086693520000121
example 1
The structural formula of the amphiphilic antibacterial peptide is RARARARA-NH 2 The above carrier is used for (RA) 3 Sequence polypeptide synthesis:
Figure BDA0004086693520000131
1) Fmoc-Ala-BDPMA (coupling of the first amino acid):
2.0g (2.2 mmol) of Compound III was taken, and the mixture was placed in a 250mL three-necked flask, and 30mL of DCM was added to the flask and dissolved with stirring. HOBt (0.59 g,4.4 mmol), HBTU (1.67 g,4.4 mmol) and Fmoc-Ala-OH (0.78 g,2.5 mmol) were taken and 5mL of DMF was added to dissolve the condensing agent and amino acid to prepare a mixed solution. The mixture was added to the flask, and 1.54mL of DIPEA (8.8 mmol) was added thereto, and the temperature was raised to 60℃and the reaction was refluxed for 10 minutes. TLC monitored the end of the reaction, after the end of the run-up, the reaction was cooled to room temperature and concentrated under reduced pressure to remove DCM. 30mL of acetonitrile was added to the residue, and the mixture was stirred well for 15min to form a suspension. The mixture was filtered and the filter cake was washed with acetonitrile and methanol. Vacuum drying at 40deg.C for 6 hr to obtain Fmoc-Ala-BDPMA.
2) H-Ala-BDPMA (Fmoc removed):
the above-mentioned product was put into a 250mL three-necked flask, 30mL of a 10% mixed solution (volume ratio) of 4-methylpiperidine/DCM was added thereto, and the mixture was dissolved by stirring sufficiently and reacted at 40℃for 20 minutes. TLC monitored the end of the reaction, and after the end of the run-up, DCM was concentrated under reduced pressure. 30mL of acetonitrile was added to the residue, and the mixture was stirred well for 15min to form a suspension. The mixture was filtered and the filter cake was washed with acetonitrile and methanol. Vacuum drying at 40deg.C for 6 hr to obtain H-Ala-BDPMA.
3) Fmoc-Arg (Pbf) -Ala-BDPMA (coupling of the second amino acid):
the above product H-Ala-BDPMA was placed in a 250mL three-necked flask, 30mL DCM was added to the flask, and the mixture was dissolved with stirring. HOBt (0.59 g,4.4 mmol), HBTU (1.67 g,4.4 mmol) and Fmoc-Arg (Pbf) -OH (1.62 g,2.5 mmol) were taken and 5mL of DMF was added to dissolve the condensing agent and amino acid to prepare a mixed solution. The mixture was added to the flask, and 1.54mL of DIPEA (8.8 mmol) was added thereto, and the temperature was raised to 60℃and the reaction was refluxed for 10 minutes. TLC monitored the end of the reaction, after the end of the run-up, the reaction was cooled to room temperature and concentrated under reduced pressure to remove DCM. 30mL of acetonitrile was added to the residue, and the mixture was stirred well for 15min to form a suspension. The mixture was filtered and the filter cake was washed with acetonitrile and methanol. Vacuum drying at 40deg.C for 6 hr to obtain Fmoc-Arg (Pbf) -Ile-BDPMA.
4) Repeating the steps of 2 to 3 to couple and deprotect the 3 rd, 4 th, 5 th, 6 th, 7 th and 8 th amino acids to obtain polypeptide chain NH 2 -Arg(Pbf)-Ala-Arg(Pbf)-Ala-Arg(Pbf)-Ala-BDPMA。
5) Cracking:
the coupled, deprotected compound was added to a 250mL three-necked flask, and 30mL TFA, TIS, and H were added to the flask 2 Mixed solution of O (TFA: TIS: H 2 O=95:2.5:2.5), the reaction was stirred at room temperature for 3 hours. TLC monitored the end of the reaction, and after the end of the run-up, the solvent was removed by concentration under reduced pressure. The residue was taken up in a volume ratio of 1:3 drops of isopropyl ether are added into the mixture and fully stirred for 15minForming a suspension. The mixture was filtered and the filter cake was washed with isopropyl ether. Vacuum drying at 40deg.C for 6 hr to obtain H-Arg-Ala-Arg-Ala-Arg-Ala-NH product 2 。
Conditions, parameters in the synthesis process of examples 2 to 12 are shown in Table 1, and other unexplained conditions, parameters, preparation methods, etc. are the same as those of example 1 except for the conditions, parameter settings given in the tables.
Examples 2 to 12 are as follows:
Figure BDA0004086693520000141
Figure BDA0004086693520000151
the Minimum Inhibitory Concentration (MIC) and the Minimum Bactericidal Concentration (MBC) are important parameters for evaluating the antimicrobial properties of an antimicrobial agent. Determination of the antibacterial activity of the above-mentioned amphiphilic antibacterial peptide: the antimicrobial peptide prepared in example 1 was first prepared as a stock solution at a concentration of 4096 μg/mL for use. Secondly, the antibacterial performance of the antibacterial peptide against the gram-negative bacteria salmonella, gram-positive bacteria enterococcus faecalis and the fungus candida albicans is evaluated by a double dilution method.
The test steps are as follows:
1) Resuscitating and activating the bacteria and formulating to a concentration of 2X 10 6 The CFU/mL bacterial suspension is reserved;
2) Taking sterile 96-well plates, and adding 100 mu L of LB bacteria basal medium into each well;
3) 100. Mu.L of antimicrobial peptide at a concentration of 4096. Mu.g/mL was added to the first well and mixed well. 100. Mu.L of the solution was aspirated from the first well and added to the second well, and mixed well. Then 100. Mu.L was aspirated from the second well into the third well, and so on, and 100. Mu.L was aspirated from the last well and discarded. At this time, the concentration of the antibacterial peptide in each well was 2048, 1024, 512, 256, 128, 64, 32, 16, 8, 4. Mu.g/mL;
4) 100. Mu.L of the prepared 2X 10 cells were then added to each well 6 CFU/mL of bacterial suspension, at which time the concentration of bacterial suspensionIs 1X 10 6 CFU/mL, concentration of antibacterial peptide in each well is 1024, 512, 256, 128, 64, 32, 16, 8, 4, 2 μg/mL;
5) 200 mu L of LB medium as a negative control, 100 mu L of LB medium as a positive control and 100 mu L of bacterial suspension;
6) And placing the inoculated 96-well plate in a 37 ℃ incubator for culturing, and testing the absorbance at the OD600 by using a microplate reader after 24 hours to obtain the minimum concentration of the antibacterial peptide for inhibiting the growth of the strain.
7) And preparing a series of concentration gradient antibacterial peptides for standby according to the minimum antibacterial concentration. Taking sterile 96-well plates, adding 100 mu L of LB bacteria basal medium into each well, adding non-antibacterial peptide into different wells according to concentration gradient, uniformly mixing, and sucking 100 mu L for discarding.
8) The inoculated 96-well plate is placed in a 37 ℃ incubator for cultivation, the inoculated 96-well plate is diluted by a culture solution after 24 hours, inoculated on an LB agar medium, and cultivated in the 37 ℃ incubator for 16-18 hours, and Colony Forming Units (CFUs) are counted. LB agar plates with only bacterial suspension without drug were set as control. The minimum sterilizing concentration (MBC) was set to a plate concentration with a sterilizing rate of 99%. FIG. 3 is a graph showing the measurement of the bactericidal concentration of the cationic antibacterial peptides obtained in examples 1 to 12 of the present invention. It can be seen that the antibacterial peptide shows a good killing effect against all of gram negative bacteria (salmonella), gram positive bacteria (enterococcus faecalis) and fungi (candida albicans), wherein example 1 only kills the above bacteria and fungi at a low concentration of 50 μg/ml.
The minimum bactericidal concentrations of the amphiphilic antimicrobial peptides of examples 1-12 are shown in the following table:
Figure BDA0004086693520000161
Figure BDA0004086693520000171
it will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (10)

1. The diarylbenzeneamines compound is characterized in that the diarylbenzeneamines compound has a structural formula shown in formula I:
Figure FDA0004086693510000011
wherein R is an alkyl chain of C12-C22.
2. The method for producing diarylbenzeneamines according to claim 1, wherein the reaction formula is as follows:
Figure FDA0004086693510000012
wherein R is a C12-C22 alkyl chain, and X is halogen;
the preparation method comprises the following steps:
a. dissolving a substance shown in a formula 1, and adding a substitution reaction reagent RX and an acid binding agent to perform substitution reaction to generate a compound 2;
b. adding the compound 2, a reducing agent and a cosolvent into a solvent, and carrying out a reduction reaction to generate a compound 3;
c. dissolving the compound 3, adding a substitution reaction reagent of carbamic acid ethyl ester and a catalyst, and carrying out substitution reaction to generate a compound 4;
d. dissolving the compound 4, adding alkali liquor and cosolvent, and carrying out hydrolysis reaction to obtain the compound shown in the formula I.
3. The method for producing diarylbenzylamine compound according to claim 2, wherein in step a, the acid-binding agent is one or a mixture of two or more of anhydrous potassium carbonate, anhydrous sodium carbonate, pyridine, diisopropylethylamine and triethylamine; the solvent is one or more than two of DMF, DMAc, DMSO, THF, NMP and toluene; the ratio of the amounts of compound 1, substitution reagent RX and acid-binding agent substance was 1.0: (4.0 to 4.5): (6.0-8.0), the substitution reaction temperature is 70-100 ℃, and the substitution reaction time is 16-20 hours.
4. The method for producing diarylbenzeneamines according to claim 2, wherein in the step b, the reducing agent is sodium borohydride, lithium aluminum hydride or borane, and the solvent is a mixture of one or more of THF, toluene and xylene; the amount of the substances of the compound 2 and the reducing agent is 1.0: (4.5-5.0), the temperature of the reduction reaction is 60-80 ℃, and the reduction reaction time is 4-6 hours.
5. The method for producing diarylbenzeneamines according to claim 2, wherein in the step c, the catalyst is methanesulfonic acid and the solvent is a mixture of one or more of THF, toluene and xylene; the ratio of the amounts of compound 3, substitution reagent urethane and catalyst material was 1.0: (2.0-2.5): (0.2-0.5), the substitution reaction temperature is 100-120 ℃, and the substitution reaction time is 3-6 hours.
6. The method for preparing diarylbenzylamine compound according to claim 2, wherein in step d, the alkali solution is sodium hydroxide, the solvent is a mixture of one or more of THF, toluene and xylene, the cosolvent is methanol or ethanol, and the ratio of the amount of compound 4 to the amount of the hydrolysis reagent is 1.0: (7.0-7.5), the hydrolysis reaction temperature is 100-120 ℃, and the hydrolysis reaction time is 16-20 hours.
7. The use of the diarylbenzenemethanamine-based compound according to claim 1 as a soluble carrier in liquid phase synthesis of polypeptide chains.
8. The application according to claim 7, characterized in that it is in particular: the method comprises the steps of taking a compound shown in a formula I as a soluble carrier, activating a carboxyl component by an activating agent, condensing the carboxyl component with amino acid through a condensing agent under an alkaline condition to remove an amino protecting group, continuously coupling the next amino acid until the synthesis of polypeptide is completed, and finally cracking the carrier to obtain a polypeptide chain which does not contain an initial terminal carrier and is amidated at the N terminal.
9. An amphiphilic antimicrobial peptide, characterized in that the amino acid sequence of the amphiphilic antimicrobial peptide is (AB) n Wherein n is an integer of 3 to 6, A is a cationic hydrophilic amino acid, and B is a hydrophobic amino acid;
preferably, the polypeptide chain is an amphiphilic antimicrobial peptide sequence (AB) n Wherein n is an integer of 3 to 6, A is a cationic hydrophilic amino acid, and B is a hydrophobic amino acid;
preferably, the cationic hydrophilic amino acid is lysine, arginine or histidine; the hydrophobic amino acid is leucine, isoleucine, phenylalanine, alanine, valine or tryptophan.
10. The use of an amphiphilic antimicrobial peptide according to claim 9 in the preparation of an antimicrobial drug;
preferably, the bacteria that the medicament can kill are enterococcus faecalis, staphylococcus aureus, methicillin-resistant staphylococcus aureus, salmonella or escherichia coli; the fungus which can be killed by the medicine is candida albicans.
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